Propofol (2,6-diisopropylphenol) is an injectable anesthetic widely used in veterinary and human medicine. Propofol has the useful attributes of rapid onset, rapid recovery, and safety in prolonged use. It has proven to be particularly suitable for maintaining long-term sedation to hospital patients in intensive care units. (I. Smith et al., Anesthesiology, 1994, 81:1005-1043.) Administration of drugs to sedated patients in a hospital setting is preferably accomplished via a parenteral route, most preferably via intravenous administration.
Propofol is a water-insoluble oil, and in order to prepare a pharmaceutically acceptable formulations suitable for parenteral administration, the active pharmaceutical ingredient must be dispersed or suspended in an isotonic, buffered, nontoxic aqueous phase. For convenience, and to reduce the opportunities for error and infection, it is preferable that the suspension or dispersion be pre-formed and immediately available for routine administration by hospital staff. This requires the formulation to be stable to storage, and it is desirable that there be no requirement for refrigerated or temperature-controlled storage.
A relatively small number of stable parental propofol formulations have been developed. A stabilized oil-free emulsion of propofol in water has been described (U.S. Pat. No. 5,637,625), but such a composition seems likely to be extremely irritating upon intravenous administration, and has not achieved commercial acceptance. Suspensions and dispersions based on a variety of synthetic carriers and amphiphilic excipients have been described (e.g., U.S. Pat. Nos. 4,056,635, 4,452,817, 6,150,423, 6,534,547, 7,034,013, 7,326,735 and 7,550,155), but synthetic carriers and excipients tend to be irritating and/or toxic at the high blood levels reached with continuous administration.
The commercially available product, marketed under the trade name DIPRIVAN™, is a less-irritating and non-toxic oil-in-water emulsion comprising 10% soy bean oil dispersed in water, with egg lecithin as a stabilizing surfactant. Propofol is present at 1% or 2% by weight, dissolved in the oil phase. Glycerol is present at about 2.25% to render the suspension isotonic. The amount of oil used presumably strikes a balance between the level of pain or irritation at the injection site, which is reduced as the propofol is diluted, and the hyperlipidemia that may result from prolonged administration of triglyceride emulsions.
Parenteral oil-in-water emulsions such as DIPRIVAN™ are based on naturally-occurring vegetable oils that are amenable to metabolism by the human body. While this is advantageous from the toxicologist's point of view, it presents a problem in that naturally-occurring triglycerides are also a ready source of metabolic energy for bacteria and fungi. A 10% isotonic emulsion of such an oil is a particularly hospitable and energy-rich environment, and accidental contamination with microorganisms, for example by insertion of a non-sterile needle into a vial of such an emulsion, is therefore likely to result in rapid microbial growth. A subsequent withdrawal of another dose from the vial can then lead to the introduction of pathogens into the bloodstream of a hospitalized patient, with dire consequences. (See: R. Nichols, J. Smith, New Engl. J. Med., 1995, 333:184-185; M. Sosis et al., Anesth. Anal., 1995, 81:132-134; J. Crowther et al., Anesth. Anal., 1996, 82:475-478; see also references therein.) For this reason, the recommended procedure in hospitals is to discard partially-used vials of DIPRIVAN™, which leads to considerable waste and potentially avoidable expense. Also, to avoid microbial contamination, intravenous ports used for DIPRIVAN™ administration should not be accessed for any other purpose, leading to the expense and risk of complications associated with additional ports and/or intravenous lines.
It would be desirable to avoid such waste, and increase safety, by effectively preventing microbial growth in propofol oil-in-water emulsions. The obvious remedy is the addition of antimicrobial preservatives, but the selection of preservatives suitable for use in oil-in-water emulsions of propofol is surprisingly limited. The chief problems are that the preservative must remain in the aqueous phase to be effective, and it must not destabilize the emulsion. It also must be pharmaceutically acceptable for intravenous administration at its antimicrobially-effective concentration; this is a particular challenge for a drug such as propofol which may be continuously administered over a period of days or weeks.
One class of suitable preservatives known in the art is chelating agents, such as EDTA (U.S. Pat. Nos. 5,714,520, 5,731,356, and 5,908,869) and DTPA (U.S. Pat. No. 6,028,108), which presumably operate by sequestering polyvalent metal ions (chiefly calcium, magnesium, and zinc) that are essential to the biochemical processes of bacteria and fungi. Unfortunately, such agents also sequester the same metal ions from the patient's bloodstream, and patients receiving high amounts of chelators require constant monitoring of plasma levels of at least zinc. Furthermore, at pharmaceutically acceptable levels, these agents slow, but do not prevent, microbial growth, and the compositions do not meet the criteria of the USP 51 Antimicrobial Preservative Effectiveness Test for Category I products.
Other preservatives that have been identified as potentially of use in soybean oil emulsions include sulfite and metabisulfite salts (U.S. Pat. Nos. 6,147,122 and 6,469,069); benzyl alcohol; benzethonium chloride, EDTA/benzyl alcohol, and sodium benzoate/benzyl alcohol (U.S. Pat. Nos. 6,140,373 and 6,140,374). Benzyl alcohol is used in some generic propofol emulsions. Although sulfite is associated with allergic reactions in some patients, generic propofol emulsions preserved with sulfite are also being marketed. None of these products are considered “antimicrobially preserved” under the USP 51 standard.
Low-oil formulations have been described (e.g., U.S. Pat. Nos. 6,100,302 and 7,097,849), but such compositions only marginally reduce microbial growth. An oil-in-water propofol emulsion featuring a combination of low oil and low pH (U.S. Pat. No. 6,399,087) has been reported to be bacteriostatic. (It is also asserted in U.S. Pat. No. 6,726,919 that there is synergy between propofol itself and a wide range of antimicrobial preservatives, but no evidence in support of such an effect was presented.)
There remains a need for oil-in-water propofol emulsions that are protected against the growth of microbial contaminants.